Deep learning-based image analysis reveals significant differences in the number and distribution of mucosal CD3 and γδ T cells between Crohn's disease and ulcerative colitis

Colon mucosae of ulcerative colitis (UC) and Crohn's disease (CD) display differences in the number and distribution of immune cells that are difficult to assess by eye. Deep learning-based analysis on whole slide images (WSIs) allows extraction of complex quantitative data that can be used to uncover different inflammatory patterns. We aimed to explore the distribution of CD3 and γδ T cells in colon mucosal compartments in histologically inactive and active inflammatory bowel disease. By deep learning-based segmentation and cell detection on WSIs from a well-defined cohort of CD (n = 37), UC (n = 58), and healthy controls (HCs, n = 33), we quantified CD3 and γδ T cells within and beneath the epithelium and in lamina propria in proximal and distal colon mucosa, defined by the Nancy histological index. We found that inactive CD had significantly fewer intraepithelial γδ T cells than inactive UC, but higher total number of CD3 cells in all compartments than UC and HCs. Disease activity was associated with a massive loss of intraepithelial γδ T cells in UC, but not in CD. The total intraepithelial number of CD3 cells remained constant regardless of disease activity in both CD and UC. There were more mucosal CD3 and γδ T cells in proximal versus distal colon. Oral corticosteroids had an impact on γδ T cell numbers, while age, gender, and disease duration did not. Relative abundance of γδ T cells in mucosa and blood did not correlate. This study reveals significant differences in the total number of CD3 and γδ T cells in particularly the epithelial area between CD, UC, and HCs, and demonstrates useful application of deep segmentation to quantify cells in mucosal compartments

Patient derived colonoids as drug testing platforms - Critical importance of oxygen concentration

Treatment of inflammatory bowel disease (IBD) is challenging, with a series of available drugs each helping only a fraction of patients. Patients may face time-consuming drug trials while the disease is active, thus there is an unmet need for biomarkers and assays to predict drug effect. It is well known that the intestinal epithelium is an important factor in disease pathogenesis, exhibiting physical, biochemical and immunologic driven barrier dysfunctions. One promising test system to study effects of existing or emerging IBD treatments targeting intestinal epithelial cells (IECs) is intestinal organoids (“mini-guts”). However, the fact that healthy intestinal epithelium is in a physiologically hypoxic state has largely been neglected, and studies with intestinal organoids are mainly performed at oxygen concentration of 20%. We hypothesized that lowering the incubator oxygen level from 20% to 2% would recapitulate better the in vivo physiological environment of colonic epithelial cells and enhance the translational value of intestinal organoids as a drug testing platform. In the present study we examine the effects of the key IBD cytokines and drug targets TNF/IL17 on human colonic organoids (colonoids) under atmospheric (20%) or reduced (2%) O2. We show that colonoids derived from both healthy controls and IBD-patients are viable and responsive to IBD-relevant cytokines at 2% oxygen. Because chemokine release is one of the important immunoregulatory traits of the epithelium that may be fine-tuned by IBD-drugs, we also examined chemokine expression and release at different oxygen concentrations. We show that chemokine responses to TNF/IL17 in organoids display similarities to inflamed epithelium in IBD-patients. However, inflammation-associated genes induced by TNF/IL17 were attenuated at low oxygen concentration. We detected substantial oxygen-dependent differences in gene expression in untreated as well as TNF/IL17 treated colonoids in all donors. Further, for some of the IBD-relevant cytokines differences between colonoids from healthy controls and IBD patients were more pronounced in 2% O2 than 20% O2. Our results strongly indicate that an oxygen concentration similar to the in vivo epithelial cell environment is of essence in experimental pharmacology

Inflammatory bowel disease

Scandinavian researchers have contributed to the present understanding of inflammatory bowel disease (IBD). Important epidemiological data and family risk factors have been reported from all the Nordic countries, original twin studies mainly from Denmark and Sweden, and relationships to cancer and surgery mostly from Sweden. In collaboration with the industry, development of medical compounds was for a long time in the front line of international research, and the Scandinavian countries participated in the clinical breakthrough of biologic treatment. At present, many Nordic centers are working in the forefront of IBD research. An increasing number of young investigators have entered the scene along with the extended distribution of University clinics and research laboratories in these countries. This presentation of IBD gives a brief overview in the fields of clinical epidemiology and molecular biology. Many areas are covered by International collaborations with partners from Nordic centers. IBD was a topic focused by the founders of Scandinavian Journal of Gastroenterology. After 50 years one may state that the journal’s history reflects important pieces of scientific knowledge within these diseases. The early scope of Johannes Myren for IBD was shown through his work in the original World Association of Gastroenterology (OMG), and after 50 years we can clearly support the view that global perspectives in IBD are increasingly important

Host-Viral Interactions in the Pathogenesis of Ulcerative Colitis

Ulcerative colitis is characterized by relapsing and remitting colonic mucosal inflammation. During the early stages of viral infection, innate immune defenses are activated, leading to the rapid release of cytokines and the subsequent initiation of downstream responses including inflammation. Previously, intestinal viruses were thought to be either detrimental or neutral to the host. However, persisting viruses may have a role as resident commensals and confer protective immunity during inflammation. On the other hand, the dysregulation of gut mucosal immune responses to viruses can trigger excessive, pathogenic inflammation. The purpose of this review is to discuss virus-induced innate immune responses that are at play in ulcerative colitis

Gammadelta T cells in Crohn's disease: a new player in the disease pathogenesis?

Crohn's disease (CD) is a chronic relapsing systemic disease affecting the gastrointestinal tract. An altered immune response to commensal intestinal bacteria takes place in genetically predisposed individuals, resulting in chronic inflammation in the gut. Several alterations in the innate immunity mechanisms have been described in recent years. Thus, the study of the immunological aspects of CD, specifically the role of lymphocytes, is a key element for understanding the pathogenesis of the disease. Gammadelta T cells (γδ T cells) constitute only a small proportion of the lymphocytes that circulate in the blood and peripheral organs and they are present mainly in the epithelia, where they can constitute up to 40% of intraepithelial lymphocytes (IEL) in the intestinal mucosa. Due to their lack of MHC restriction and their unique plasticity and immune regulating properties they are considered key cells in the first line of defense against infections and in wound healing in the gut. Although there is growing experimental and clinical evidence of their implication in inflammatory bowel disease (IBD), including CD, their clinical relevance is still unclear. In this review, we address the possible involvement of γδ T cells in the pathogenesis of CD, reviewing their role against infections and in inflammation and the current evidence suggesting their implication in CD, offering a novel potential target for immunotherapy in IBD

Acupuncture versus usual care for postoperative nausea and vomiting in children after tonsillectomy/adenoidectomy: a pragmatic, multicenter, double-blinded, randomized trial

Objectives To investigate the effect of a standardised acupuncture on nausea and vomiting in children after tonsillectomy with or without adenoidectomy when possible placebo effects were precluded. Methods A pragmatic, multicentre, doubleblinded, randomised controlled trial. The study was conducted over 10 months in 2012–2013 at three ambulatory clinics. Two hundred and eighty-two children, age 1–11 years, American Society of Anesthesiologists grade ≤II, were included. To equalise expectancy effects, all parents were told that their child would receive acupuncture. However, children were randomly allocated to perioperative bilateral needling acupuncture at PC6, depth 7 mm, mean time 17 min (SD 5–45) during anaesthesia plus usual care, or to usual care only. The regional ethics committee approved this approach. Primary endpoints were nausea and vomiting 24 h postoperatively.Results This study did not demonstrate any effect of acupuncture (95% CI) compared with standard care. The overall vomiting in the acupuncture and usual-care groups was 44.2% and 47.9%, respectively. Nausea was experienced by 31.7% in the acupuncture group and by 32.6% in the usual-care group. The test power was acceptable for comparisons of vomiting. Conclusions The findings suggest that when controlling for possible placebo effects standardised PC6 acupuncture needling during anaesthesia without further stimulation of PC6 is not effective in reducing nausea and vomiting in children after tonsillectomy with or without adenoidectomy. Future studies should investigate acupuncture treatment which balances adequate dose and technique and a feasible, child-friendly acupuncture treatment

Acupuncture versus usual care for postoperative nausea and vomiting in children after tonsillectomy/adenoidectomy: a pragmatic, multicenter, double-blinded, randomized trial

Objectives To investigate the effect of a standardised acupuncture on nausea and vomiting in children after tonsillectomy with or without adenoidectomy when possible placebo effects were precluded. Methods A pragmatic, multicentre, doubleblinded, randomised controlled trial. The study was conducted over 10 months in 2012–2013 at three ambulatory clinics. Two hundred and eighty-two children, age 1–11 years, American Society of Anesthesiologists grade ≤II, were included. To equalise expectancy effects, all parents were told that their child would receive acupuncture. However, children were randomly allocated to perioperative bilateral needling acupuncture at PC6, depth 7 mm, mean time 17 min (SD 5–45) during anaesthesia plus usual care, or to usual care only. The regional ethics committee approved this approach. Primary endpoints were nausea and vomiting 24 h postoperatively.Results This study did not demonstrate any effect of acupuncture (95% CI) compared with standard care. The overall vomiting in the acupuncture and usual-care groups was 44.2% and 47.9%, respectively. Nausea was experienced by 31.7% in the acupuncture group and by 32.6% in the usual-care group. The test power was acceptable for comparisons of vomiting. Conclusions The findings suggest that when controlling for possible placebo effects standardised PC6 acupuncture needling during anaesthesia without further stimulation of PC6 is not effective in reducing nausea and vomiting in children after tonsillectomy with or without adenoidectomy. Future studies should investigate acupuncture treatment which balances adequate dose and technique and a feasible, child-friendly acupuncture treatment

Effect of the histamine-2 agonist impromidine on stem cell proliferation of rat oxyntic mucosa

Background: The trophic effect of gastrin on the histamine-containing enterochromaffin-like cell is pronounced but on the stem cell of the oxyntic mucosa it is only modest. In the rat, gastrin stimulates acid secretion mainly by releasing histamine from enterochromaffin-like cells. This study was designed to test the hypothesis that the trophic effect of gastrin on stem cells is also mediated by histamine released from the enterochromaffin-like cell. Methods: We stimulated rats with the histamine-2 agonist impromidine. Impromidine, 0.2mg/h, was given for 2 days by subcutaneously implanted osmotic minipumps, and the trophic effect on stem cells was assessed by incorporation of tritiated thymidine. Results: The plasma gastrin concentrations were 33.9 (9.4) pM and 27.3 (6.0) pM, and the stem cell labelling index values were 5.92 (1.94) and 8.09 (3.78) in the controls and impromidine-stimulated animals, respectively (mean value (SD)). These differences were not statistically significant. Conclusion: The present study provides no evidence that histamine-2 receptors mediate a trophic effect on the stem cell of the rat oxyntic mucosa. © 1995 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.SCOPUS: ar.jinfo:eu-repo/semantics/publishe